Process for manufacturing glatiramer acetate product

ABSTRACT

The patent provides a process of preparing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container comprising the steps of:
         (i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;   (ii) filtering the aqueous pharmaceutical solution at a temperature of from above 0° C. up to 17.5° C. to produce a filtrate; and   (iii) filling the suitable container with the filtrate obtained after performing step (ii), so as to thereby prepare the pharmaceutical preparation of glatiramer acetate and mannitol in the suitable container.       

     This patent further provides an aqueous pharmaceutical solution comprising 40 mg/ml glatiramer acetate and 40 mg/ml mannitol, wherein the aqueous pharmaceutical solution
         a) has a viscosity in the range of 2.0-3.5 cPa; or   b) has an osmolality in the range of 275-325 mosmol/Kg.       

     This patent also provides a prefilled syringe, an automated injector and a method of treatment of a human patient.

The disclosures of various publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Glatiramer acetate (GA), the active ingredient of Copaxonee, consists ofthe acetate salts of synthetic polypeptides, containing four naturallyoccurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, andL-lysine with an average molar fraction of 0.141, 0.427, 0.095, and0.338, respectively. The peak average molecular weight of glatirameracetate is between 5,000 and 9,000 daltons. Glatiramer acetate isidentified by specific antibodies (Copaxone, Food and DrugAdministration Approved Labeling (Reference ID: 3443331) [online], TEVAPharmaceutical Industries Ltd., 2014 [retrieved on Dec. 24, 2014],Retrieved from the Internet: <URL:www.accessdata.fda.gov/drugsatfda_docs/labe1/2014/020622s0891b1.pdf>)

Chemically, glatiramer acetate is designated L-glutamic acid polymerwith L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structuralformula is:

(Glu,Ala,Lys,Tyr)x.X CH3COOH

(C₅R₃NO₄ .C₃H₇NO₂.C₆H₁₄N₂O₂.C₉H₁₁NO₃)x.xC₂H₄O₂

CAS-147245-92-9

Copaxone® is a clear, colorless to slightly yellow, sterile,nonpyrogenic solution for subcutaneous injection. Each 1 mL of Copaxone®solution contains 20 mg or 40 mg of GA, the active ingredient, and 40 mgof mannitol. The pH of the solutions is approximately 5.5 to 7.0.Copaxone® 20 mg/mL in a prefilled syringe (PFS) is an approved product,the safety and efficacy of which are supported by over two decades ofclinical research and over a decade of post-marketing experience.Copaxone® 40 mg/mL in a PFS was developed as a new formulation of theactive ingredient GA. Copaxone® 40 mg/ml, is a prescription medicineused for the treatment of people with relapsing forms of multiplesclerosis (Copaxone, Food and Drug Administration Approved Labeling(Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd.,2014 [retrieved on Dec. 24, 2014], Retrieved from the Internet: <URL:www.accessdata.fda.gov/drugsatfda_docs/labe1/2014/02062250891b1.pdf_(>))

It is an object of the present invention to provide an improved processfor manufacturing GA drug products.

SUMMARY OF THE INVENTION

The patent provides a process of preparing a pharmaceutical preparationof glatiramer acetate and mannitol in a suitable container comprisingthe steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

This patent also provides a prefilled syringe containing 40 mg ofglatiramer acetate and 40 mg mannitol, which syringe is prepared by aprocess of the invention.

This patent further provides an aqueous pharmaceutical solutioncomprising 40 mg/ml glatiramer acetate and 40 mg/ml mannitol, whereinthe aqueous pharmaceutical solution

-   -   a) has a viscosity in the range of 2.0-3.5 cPa; or    -   b) has an osmolality in the range of 275-325 mosmol/Kg.

This patent also provides a prefilled syringe containing 1 ml of anaqueous pharmaceutical solution prepared by a process of the invention.

This patent also provides an automated injector comprising the prefilledsyringe prepared by a process of the invention.

Aspects of the present invention relate to a method of treatment of ahuman patient suffering from a relapsing form of multiple sclerosiscomprising administration to the human patient of three subcutaneousinjections of a 40 mg/ml dose of glatiramer acetate per week using theprefilled syringe of this invention, using the aqueous pharmaceuticalsolution of this invention, or using the automated injector of thisinvention so as to treat the human patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Schematic description of filtration process by cooled receivingvessel and filter housing.

FIG. 2. Schematic description of filtration process by heat exchangerand cooled filter housing.

FIG. 3. Pressure record for Experiment No. 1. * Filtration of GAsolution at controlled room temperature was stopped and the remainingsolution was transferred to the cooled receiving vessels.

FIG. 4. Pressure record for Experiment No. 2. * Pauses of 3 hours and 5hours for GA solutions filtered at controlled room temperature and atreduced temperature, respectively. ** Pause of 10 hours for both GAsolutions. *** Filtration of GA solution at controlled room temperaturewas stopped. Remaining GA solution was filtered at reduced temperature.

FIG. 5. Pressure record for Experiment No. 3.

FIG. 6. Schematic description of filtration process by cooledcompounding vessel and cooled filter housings on both Filter A andFilter B.

FIG. 7. Schematic description of filtration process by heat exchangerand cooled filter housings on both Filter A and Filter B.

FIG. 8. Schematic description of filtration process by cooled filterhousing on only Filter B.

FIG. 9. Schematic description of filtration process by cooled filterhousings on both Filter A and Filter B.

FIG. 10. Schematic description of filtration process by cooledcompounding vessel.

FIG. 11. Schematic description of filtration process by cooled receivingvessel.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In some embodiments the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, or a firstfilter and a second filter.

In some embodiments the process further comprises the step of reducingthe temperature of the second filter to a temperature from above 0° C.up to 17.5° C.

In some embodiments the process further comprises the step of reducingthe temperature of the aqueous pharmaceutical solution to a temperaturefrom above 0° C. up to 17.5° C. before passing through the secondfilter.

In some embodiments the filtering step (ii) further comprises the stepof receiving the aqueous pharmaceutical solution filtered through thefirst filter in a receiving vessel.

In some embodiments the process further comprises the step of reducingthe temperature of the aqueous pharmaceutical solution to a temperaturefrom above 0° C. up to 17.5° C. after leaving the receiving vessel andbefore entering into the second filter.

In some embodiments the process further comprises the step of reducingthe temperature of the aqueous pharmaceutical solution to a temperaturefrom above 0° C. up to 17.5° C. while in the receiving vessel.

In some embodiments the process further comprises the step of reducingthe temperature of the first filter to a temperature from above 0° C. upto 17.5° C.

In some embodiments the process further comprises the step of reducingthe temperature of the aqueous pharmaceutical solution to a temperaturefrom above 0° C. up to 17.5° C. before passing through the first filter.

In some embodiments the obtaining step (i) comprises compounding theaqueous pharmaceutical solution in a compounding vessel.

In some embodiments the process further comprises the step of reducingthe temperature of the aqueous pharmaceutical solution to a temperaturefrom above 0° C. up to 17.5° C. after leaving the compounding vessel andbefore entering into the first filter.

In some embodiments the process further comprises the step of reducingthe temperature of the aqueous pharmaceutical solution to a temperaturefrom above 0° C. up to 17.5° C. while in the compounding vessel.

In some embodiments the aqueous pharmaceutical solution is passedthrough the second filter at a rate of 3-25 liters/hour.

In some embodiments the aqueous pharmaceutical solution is passedthrough the second filter preferably at a rate of 3-22 liters/hour.

In some embodiments the aqueous pharmaceutical solution is passedthrough the second filter more preferably at a rate of 3-15 liters/hour.

In some embodiments the aqueous pharmaceutical solution is passedthrough the second filter at a rate more preferably at a rate of 3-10liters/hour.

In some embodiments the pressure during the filtering step (ii) and thepressure during the filling step (iii) is maintained below 5.0 bar.

In some embodiments the pressure during the filtering step (ii) and thepressure during the filling step (iii) is maintained preferably below3.0 bar.

In some embodiments the pressure during the filtering step (ii) and thepressure during the filling step (iii) is maintained below 2.0 bar.

In some embodiments the temperature of the aqueous pharmaceuticalsolution is between 0° C. and 14° C., or the temperature of the aqueouspharmaceutical solution is reduced to a temperature between 0° C. and14° C.

In some embodiments the temperature of the aqueous pharmaceuticalsolution is between 0° C. and 12° C., or the temperature of the aqueouspharmaceutical solution is reduced to a temperature between 0° C. and12° C.

In some embodiments the temperature of the aqueous pharmaceuticalsolution is 2° C. - 12° C., or the temperature of the aqueouspharmaceutical solution is reduced to 2° C.-12° C.

In some embodiments the temperature of the aqueous pharmaceuticalsolution is 4° C.-12° C., or the temperature of the aqueouspharmaceutical solution is reduced to 4° C.-12° C.

In some embodiments the filtering is performed using a sterilizingfilter having a pore size of 0.2 μm or less, wherein the first, thesecond or both filters are a sterilizing filter having a pore size of0.2 μm or less.

In some embodiments the pharmaceutical preparation in the suitablecontainer is an aqueous pharmaceutical solution comprising 20 mg/mlglatiramer acetate and 40 mg/ml mannitol.

In some embodiments the pharmaceutical preparation in the suitablecontainer is an aqueous pharmaceutical solution comprising 40 mg/mlglatiramer acetate and 40 mg/ml mannitol.

In some embodiments the pharmaceutical preparation in the suitablecontainer is an aqueous pharmaceutical solution having a pH in the rangeof 5.5-7.0.

In some embodiments the pharmaceutical preparation in the suitablecontainer is an aqueous pharmaceutical solution which is a sterilizedaqueous solution which has been sterilized by filtration and withoutsubjecting the aqueous pharmaceutical solution to heat, chemicals, orradiation exposure.

In some embodiments the pharmaceutical preparation is a lyophilizedpowder of glatiramer acetate and mannitol.

In some embodiments the process further comprises a step of lyophilizingthe filtrate after it has been filled into the suitable container so asto form a lyophilized powder of glatiramer acetate and mannitol in thesuitable container.

In some embodiments the suitable container is a syringe, vial, ampoule,cartridge or infusion.

In some embodiments the suitable container is a syringe.

In some embodiments the syringe contains 1 ml of an aqueouspharmaceutical solution.

This invention provides a prefilled syringe containing 40 mg ofglatiramer acetate and 40 mg mannitol, which syringe is prepared by aprocess of the invention.

According to any embodiment of the prefilled syringe disclosed herein,the prefilled syringe contains 1 ml of an aqueous pharmaceuticalsolution of 40 mg/ml of glatiramer acetate and 40 mg/mi mannitol.

According to any embodiment of the prefilled syringe disclosed herein,the aqueous pharmaceutical solution

-   -   a) has a viscosity in the range of 2.0-3.5 cPa; or    -   b) has an osmolality in the range of 270-330 mosmol/Kg.

According to any embodiment of the prefilled syringe disclosed herein,the aqueous pharmaceutical solution

-   -   a) has a viscosity in the range of 2.2-3.0 cPa; or    -   b) has an osmolality in the range of 275-325 mosmol/Kg.

This invention provides an aqueous pharmaceutical solution comprising 40mg/ml glatiramer acetate and 40 mg/ml mannitol, wherein the aqueouspharmaceutical solution

-   -   a) has a viscosity in the range of 2.0-3.5 cPa; or    -   b) has an osmolality in the range of 275-325 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution has a viscosity in the range of2.0-3.5 cPa.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution has a viscosity in the range of2.61-2.92 cPa.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution has an osmolality in the range of275-325 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution has an osmolality in the range of300-303 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution comprises glatiramer acetate havinga viscosity in the range of 2.3-3.2 cPa.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution comprises glatiramer acetate havinga viscosity in the range of 2.6-3.0 cPa.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution comprises glatiramer acetate havingan osmolality in the range of 290-310 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution comprises glatiramer acetate havingan osmolality in the range of 295-305 mosmol/Kg.

According to some embodiments of the aqueous pharmaceutical solution,the aqueous pharmaceutical solution has a pH in the range of 5.5-7.0.

This invention provides a prefilled syringe containing 1 ml of anaqueous pharmaceutical solution prepared by the invention.

This invention provides an automated injector comprising the prefilledsyringe prepared by the invention.

This invention provides a method of treatment of a human patientsuffering from a relapsing form of multiple sclerosis comprisingadministration to the human patient of three subcutaneous injections ofa 40 mg/ml dose of glatiramer acetate per week using the prefilledsyringe of this invention, using the aqueous pharmaceutical solution ofthis invention, or using the automated injector of this invention so asto treat the human patient.

In some embodiments, the human patient is suffering fromrelapsing-remitting multiple sclerosis.

In some embodiments, the human patient has experienced a first clinicalepisode and has MRI features consistent with multiple sclerosis.

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In an embodiment, the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, and a secondfilter.

In an embodiment, the obtaining step (i) comprises compounding theaqueous pharmaceutical solution in a compounding vessel.

In an embodiment, the process further comprises the step of reducing thetemperature of the aqueous pharmaceutical solution to a temperature fromabove 0° C. up to 17.5° C. while in the compounding vessel.

In an embodiment, the process further comprises the step of reducing thetemperature of the first filter to a temperature from above 0° C. up to17.5° C.

In an embodiment, the process further comprises the step of reducing thetemperature of the second filter to a temperature from above 0° C. up to17.5° C.

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In an embodiment, the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, and a secondfilter.

In an embodiment, the obtaining step (i) comprises compounding theaqueous pharmaceutical solution in a compounding vessel.

In an embodiment, the process further comprises the step of reducing thetemperature of the aqueous pharmaceutical solution to a temperature fromabove 0° C. up to 17.5° C. after leaving the compounding vessel andbefore entering into the first filter.

In an embodiment, the process further comprises the step of reducing thetemperature of the first filter to a temperature from above 0° C. up to17.5° C.

In an embodiment, the process further comprises the step of reducing thetemperature of the second filter to a temperature from above 0° C. up to17.5° C.

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In an embodiment, the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, and a secondfilter.

Tn an embodiment, the process further comprises the step of reducing thetemperature of the second filter to a temperature from above 0° C. up to17.5° C.

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In an embodiment, the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, and a secondfilter.

In an embodiment, the process further comprises the step of reducing thetemperature of the first filter to a temperature from above 0° C. up to17.5° C.

In an embodiment, the process further comprises the step of reducing thetemperature of the second filter to a temperature from above 0° C. up to17.5° C.

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In an embodiment, the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, and a secondfilter.

In an embodiment, the obtaining step (i) comprises compounding theaqueous pharmaceutical solution in a compounding vessel.

In an embodiment, the process further comprises the step of reducing thetemperature of the aqueous pharmaceutical solution to a temperature fromabove 0° C. up to 17.5° C. while in the compounding vessel.

This invention provides a process of preparing a pharmaceuticalpreparation of glatiramer acetate and mannitol in a suitable containercomprising the steps of:

-   -   (i) obtaining an aqueous pharmaceutical solution of glatiramer        acetate and mannitol;    -   (ii) filtering the aqueous pharmaceutical solution at a        temperature of from above 0° C. up to 17.5° C. to produce a        filtrate; and    -   (iii) filling the suitable container with the filtrate obtained        after performing step (ii), so as to thereby prepare the        pharmaceutical preparation of glatiramer acetate and mannitol in        the suitable container.

In an embodiment, the filtering step (ii) comprises filtering theaqueous pharmaceutical solution through a first filter, and a secondfilter.

In an embodiment, the filtering step (ii) further comprises the step ofreceiving the aqueous pharmaceutical solution filtered through the firstfilter in a receiving vessel.

In an embodiment, the process further comprises the step of reducing thetemperature of the aqueous pharmaceutical solution to a temperature fromabove 0° C. up to 17.5° C. while in the receiving vessel.

Automated Injection Device

The mechanical workings of an automated injection assisting device canbe prepared according to the disclosure in European applicationpublication No. EP0693946 and U.S. Pat. No. 7,855,176, which areincorporated herein by reference.

All combinations of the various elements described herein are within thescope of the invention.

Definitions

As used herein, “glatiramer acetate” is a complex mixture of the acetatesalts of synthetic polypeptides, containing four naturally occurringamino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. Thepeak average molecular weight of glatiramer acetate is between 5,000 and9,000 daltons. Chemically, glatiramer acetate is designated L-glutamicacid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt).Its structural formula is:

(Glu,Ala,Lys,Tyr)x.X CH3COOH

(O5H9NO4.C3H7NO2.C6H14N2O2.C9H11NO3) x.x C2A402

CAS-147245-92-9

As used herein “glatiramer acetate drug substance” is the glatirameracetate active ingredient prior to its formulation into a glatirameracetate drug product.

As used herein, a “glatiramer acetate drug product” is a formulation forpharmaceutical use which contains a glatiramer acetate drug substance.Copaxone® is a commercial glatiramer acetate drug product manufacturedby TEVA Pharmaceutical Industries Ltd. (Israel), which is described inCopaxone, Food and Drug Administration Approved Labeling (Reference ID:3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [retrievedon Dec. 24, 2014], Retrieved from the Internet: CURL:www.accessdata.fda.gov/drugsatfda docs/label/2014/020622s0891b1.pdf>,the contents of which are hereby incorporated by reference. Copaxone® isavailable as 20 mg/mL administered once per day, and/or 40 mg/mladministered three times per week.

As used herein, a “sterilizing filter” is a filter with a pore size of0.2 μm or less which will effectively remove microorganisms.

By any range disclosed herein, it is meant that all hundredth, tenth andinteger unit amounts within the range are specifically disclosed as partof the invention. Thus, for example, 1 mg to 50 mg means that 1.1, 1.2 .. . 1.9; and 2, 3 . . . 49 mg unit amounts are included as embodimentsof this invention.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

Experimental Details Methods

Glatiramer Acetate (GA) Injection 40 mg/mL in a prefilled syringe (GAinjection 40 mg/mL in PFS or Copaxone® 40 mg/mL) was developed as a newformulation of the active ingredient glatiramer acetate, which is alsoused in the marketed product Copaxone® 20 mg/mL solution for injectionin a prefilled syringe. Copaxone® 40 mg/mL is to be administered threetimes a week by subcutaneous injection to patients with RelapsingRemitting Multiple Sclerosis. The new formulation is based on theformulation of the marketed Copaxone® 20 mg/ml, solution for injectionin a prefilled syringe. Copaxone® 20 mg/mL is an approved product, thesafety and efficacy of which are supported by over two decades ofclinical research and over a decade of post-marketing experience. Theonly difference between the formulations is the double amount of theactive substance used, which results in a solution with double theconcentration of giatiramer acetate (40 mg/mL vs. 20 mg/mL). The amountof mannitol in both Copaxone® formulations remains unchanged (40 mg/mL).

The compositions of Copaxone® 20 mg/mL and Copaxone® 40 mg/mL aredetailed in Table 1.

TABLE 1 Compositions of Copaxone ® 20 mg/mL and Copaxone ® 40 mg/mLCopaxone ® 20 mg/mL Copaxone ® 40 mg/mL Components Content per mLGlatiramer Acetate¹ 20.0 mg 40.0 mg Mannitol USP/Ph. 40.0 mg 40.0 mgEur. Water for Injection q.s.to 1.0 mL q.s. to 1.0 mL USP/Ph. Eur/JP¹Calculated on the dry basis and 100% assay

Studies were conducted in order to verify that the formulation ofCopaxone® 40 mg/mL, its manufacturing process and chemical, biologicaland microbiological attributes are appropriate for commercialization.Studies were also conducted to confirm the suitability of the proposedcontainer closure system for packaging Copaxone® 40 mg/mL.

Mannitol was chosen as the tonicity agent for the initially formulatedCopaxone® (freeze dried product, reconstituted prior to administration)as it is also a bulking agent. When the currently marketed ready-to-useformulation of Copaxone® 20 mg/mL solution for injection prefilledsyringe was developed, mannitol was used in this formulation as well, asthe osmoregulator. Finally, when the new 40 mg/mL formulation wasdeveloped, based on the Copaxone® 20 mg/mL formulation, mannitolremained as the osmoregulator.

Mannitol is widely used in parenteral formulations as an osmo-regulator.It is freely soluble in water and stable in aqueous solutions. Mannitolsolutions may be sterilized by filtration. In solution, mannitol is notaffected by atmospheric oxygen in the absence of catalysts. Theconcentration of mannitol in the Copaxone® 40 mg/mL is 40 mg/mL.Maintaining the mannitol concentration in Copaxone® 40 mg/mL resulted inan essentially isotonic solution.

Water for injection (WFI) is the most widely used solvent and inertvehicle in parenteral formulations. Water is chemically stable in allphysical states. It is the base for many biological life forms, and itssafety in pharmaceutical formulations is unquestioned.

EXAMPLE 1

The manufacturing process of Copaxonee 40 mg/mL comprises:

-   -   Compounding a bulk solution of GA and mannitol in water for        injections (WEI).    -   Sterilizing filtration of the bulk solution yielding the sterile        GA solution in bulk.    -   Aseptic filling of sterile bulk solution into syringe barrels        and stoppering.    -   Inspection and final assembly of the filled syringes.

Initially, filtration of bulk solution from the compounding vessel wasperformed through a sequential filter train consisting of two sequentialsterilizing filters (filters named A₁ and A₂, respectively) to areceiving vessel. From the receiving vessel it was transferred to theintermediate vessel in the filling machine and further through dosingpumps and needles into prefilled syringes. However, due to a HealthAuthority request to place the sterilizing filter as close as possibleto the filling point, the second sterilizing filter was moved betweenthe receiving and intermediate vessels. In the current filtration train,the first sterilizing filter was named Filter A, and the secondrelocated sterilizing filter was named Filter B. See, FIG. 1.

In line with the process for the approved Copaxonee 20 mg/mLformulation, all processing steps of the new Copaxonee 40 mg/mLformulation were originally conducted at controlled room temperature.However, filtration of the higher concentration solution resulted in apressure build-up on the second filter, Filter B. Despite the observedpressure increase on Filter B, a high-quality drug product could beobtained by filtration of GA 40 mg/mL at controlled room temperature, asconfirmed by release and stability data. Nevertheless, an improvedfiltration process was needed which avoided the build-up on the secondfilter.

Flow rate for fluids can be defined by the differential pressure, andinversely moderated by viscosity. Viscosity, in turn, is usuallyreciprocal in relation to temperature (Meltzer and Jornitz, Filtrationand Purification in the Biopharmaceutical Industry, Second Edition, CRCPress, 2007, page 166). Increasing the temperature of a solution willnormally decrease the viscosity, thereby enhancing the flow rate.

In an attempt to solve the pressure build-up problem on the secondfilter, the temperature condition of the filtration was raised abovecontrolled room temperature. Although the viscosity decreased, thefilterability decreased, resulting in a failed attempt.

The following studies were performed:

-   -   Filter Validation Study: Determination of ranges for the        manufacturing parameters related to sterilizing Filter A and        sterilizing Filter B of the bulk solution, as well as        confirmation of filter compatibility with the drug product.    -   Filtration Process: Selection of the sterilizing filtration        conditions best suitable for the manufacturing process and the        quality of the drug product.        Filters Used for Copaxone® 20 mg/mL and Copaxone® 40 mg/mL        Manufacturing

The manufacturing process of Copaxone® 40 mg/mL was based on the processused to produce the marketed Copaxone® 20 mg/mL solution for injectionin a prefilled syringe. Therefore the same filters used for filtrationof marketed product were used.

Two sterilizing filters were used, each of which having a pore size of0.2 μm or less, to effectively remove microorganisms. Sterilization isachieved only by filtration using sterilizing filters and not by usingother methods, e.g. sterilization is achieved without using heat,chemicals, or radiation exposure.

Filter Validation Study—Confirmation and Setting of ParametersAssociated with Filter Compatibility and with Sterilizing Filtration

The following tests were performed in order to confirm the filtervalidity:

-   -   Extractables testing—assessment of extractables released from        the filter upon steam sterilization and their removal from the        filter by a model solvent, thus assessing the volume to be        discarded after the filtration through the Filter B, prior to        beginning of the aseptic filling.    -   Compatibility/adsorption testing—assessment of the chemical        compatibility of GA 20 mg/mL and GA 40 mg/mL solution with the        filter material and the extent of its adsorption to the filter,        thus assessing the volume to be discarded after the filtration        through Filter B, prior to beginning of the aseptic filling in        order to provide assay within specifications.    -   Residual effect—To ensure that no significant residual GA 20        mg/mL or GA 40 mg/mL solution that might affect the post use        integrity test remains on the filter after filtration.    -   Bacterial challenge—To ensure that the filtration process does        not affect the ability of the filter to provide a sterile        solution.

The above tests were conducted using maximum pressure (up to 5.0 bar).The validation study demonstrated that the selected filtration system iscapable of providing a high quality Copaxone® 20 mg/mL and Copaxone® 40mg/mL.

Given the strict and well-defined operational and equipment parametersof the GA 40 mg/mL solution filtration process, a plan to mitigate thepotential increase in pressure by reducing the filtration temperaturewas developed.

Without much expectations, it was decided to examine the filtrationprocess of GA 40 mg/mL sterile bulk solution through Filter B underreduced temperature conditions, using the same filters and filtrationtrain as for the filtration at controlled room temperature.

Accordingly, experiments were performed in order to compare thefiltration of GA 40 mg/ml, sterile bulk solution through Filter B underreduced temperature and controlled room temperature in the productionenvironment and to ensure that there is no difference with regard to thequality and stability profiles of the filtered solutions. In allexperiments, the sterile bulk solution was prepared according to thestandard compounding and filtration train (see FIG. 1) and filteredthrough two filters: Filter A and Filter B.

The experiments tested two different cooling technologies (cooledreceiving vessels vs heat exchanger) with cooled filter. The studies areschematically depicted in FIG. 1 and FIG. 2. Further details about theseexperiments and their outcomes are provided hereafter.

Filtration Process—Experiment No. 1

The objective of Experiment No. 1 was to compare the filterability of abatch of bulk solution held and filtered through Filter B at eithercontrolled room temperature or under reduced temperature conditions(cooling by double-jacketed receiving vessel and cooled Filter Bhousing).

The study is schematically depicted in FIG. 1. The experimental designand the obtained results are summarized in Table 2 and FIG. 3.

TABLE 2 Experimental Design and Results for Experiment No. 1. ExperimentReduced Temperature Controlled Room Outline Filtration TemperatureFiltration Compounding According to standard manufacturing procedure¹Holding time in 13 hours 13 hours the receiving vessel Temperature of6.6-10.7° C.² 17.8-24.6° C. solution held in the receiving vesselPlanned regimen Intermittent filtration: for filtration Stage I - 5filtration steps of filtration of though Filter B³ about 10 liters ofbulk solution - followed by pauses of about 50 minutes each, followed bya pause of 5 hours. Stage II - 4 filtration steps of filtration of about10 liters of bulk solution - followed by pauses of about 50 minuteseach, followed by a pause of about 10 hours. Stage III - Filtration ofremaining solution. Total volume of About 125 L. Filtration About 85liters. bulk solution was completed. Filtration was stopped filtered dueto increase in pressure on Filter B. ¹One bulk solution was prepared anddivided into two portions. Bulk solution size: 230 liters. Filtration ofsolution at controlled room temperature was stopped after 85 liters havebeen pushed through the filter due to increased pressure and theremaining solution was transferred to the cooled receiving vessels. ²Thetemperature increased (to 14.9° C.) once during the filtration followingthe addition of the remaining solution kept at ambient temperature. ³Thefiltrations were carried out in parallel.

Surprisingly, filtration at reduced temperature allowed filtration to becompleted without the pressure increase associated with filtration atcontrolled room temperature.

EXAMPLE 2

Filtration Process—Experiment No. 2

The first objective of Experiment No. 2 was to evaluate whether localcooling of GA 40 mg/mL solution using a Heat Exchanger (HE) couldimprove the filterability through cooled Filter 3 compared tofilterability of the same bulk solution at controlled room temperature.

The second objective of Experiment No. 2 was to confirm that there is nodifference in the quality of the drug product filled into syringes atcontrolled room temperature and drug product filled into syringes atreduced temperature.

Cooling by heat exchanger was evaluated as it seemed to be much easierto steam sterilize than using the double jacketed receiving vessels. TheHE was located between the receiving vessel and Filter B. Consequently,as opposed to Experiment No. 1 (in which the solution was cooled by thedouble-jacketed receiving vessels following filtration through Filter Aand kept cooled prior to filtration through Filter B), the solution inthis experiment was held at controlled room temperature prior tofiltration of the locally cooled (by HE) GA solution through Filter B.

The study is schematically depicted in FIG. 2. The experimental designand the obtained results are summarized in Table 3. The pressureobserved over the course of the filling process of Experiment No. 2 isshown in FIG. 4.

TABLE 3 Experimental Design and Results for Experiment No. 2. ExperimentReduced Temperature Controlled Room Outline Filtration TemperatureFiltration Compounding According to standard manufacturing procedure¹Filtration into a Filtration of all the bulk solution through receivingvessel Filter A into a receiving vessel held at controlled roomtemperature Temperature of Controlled room temperature solution held inthe receiving vessel Holding time in 19 hours the receiving vesselPlanned regimen The solution is locally The solution is for filtrationcooled as it is filtered through Filter through Filter B transferredthrough a B at controlled room HE and filtered through temperature.Three cooled Filter B. Three consecutive filtration consecutivefiltration and filling stages. and filling stages. About 5 hours breakAbout 3 hours break between Stage I and between Stage I and Stage II andabout 10 Stage II and about 10 hours break between hours break betweenStage II and Stage III. Stage II and Stage III. Temperature of 6.4-12°C. No use of HE solution trans- ferred, through the HE Duration, of 24hours 19 hours filtration through Filter B² Temperature of 5.7-8.8° C.Ambient temperature solution trans- ferred through Filter B Total volumeof 154 L 63 L³ bulk solution filtered and filled into syringes Storageconditions Long term (2-8° C.) during stability Accelerated (25° C./60%RH) - completed 6 months studies Stress (40° C./75% RH) - completed 3months Stability data The stability data showed that the drug producthas a similar stability profile when it is filtered at controlled roomtemperature or under reduced temperature conditions. Both filtrationprocesses demonstrate similar impurity profiles. ¹One bulk solution wasprepared and divided into two portions. Bulk solution size: 230 liters.²Both filtration processes (reduced and controlled room temperature)were carried out in parallel for comparison. At each stage, filtrationwas carried out at controlled room temperature, followed by filtrationat reduced temperature. ³Filtration of solution at controlled roomtemperature was stopped due to pressure increase and the remainingsolution was filtered at reduced temperature.

EXAMPLE 3

Filtration Process—Experiment No. 3

One objective of Experiment No. 3 was to confirm whether cooling of GA40 mg/mL bulk solution prior to filtration, using HE and cooled filterhousing, allows filtration and filling of batches of 130 L size withinvarious manufacturing regimens.

Another objective of Experiment No. 3 was to evaluate the influence ofholding time at various stages of the manufacturing process onfilterability of GA 40 mg/mL.

Another objective of Experiment 3 was to demonstrate with a high degreeof assurance that locally cooled GA 40 mg/mL solution filtered throughFilter B is not different in its quality and stability profile from GA40 mg/mL solution filtered through Filter B at controlled roomtemperature conditions with regard to pre-determined parameters andlimits.

A series of three batches of bulk solution, manufactured at variousregimens, were prepared. Each bulk solution was prepared from anidentical combination of the same three drug substance batches.

The experimental design and results are summarized in Table 4.

TABLE 4 Experimental Design and Results for Experiment No. 3 ControlledControlled Reduced Room Reduced Room Temperature Temperature TemperatureTemperature Experiment Outline Filtration Filtration FiltrationFiltration Batch No. A A-2¹ B C Compounding Standard Standard StandardStandard compounding compounding compounding compounding Batch sizeFirst 130 L Remaining 50 L 180 L 180 L from bulk from bulk solution Asolution A Holding time in the 4 hours 4 hours (same 8 hours 3.5 hourscompounding vessel² bulk solution as A) Holding time in the 1.5 hours10.5 hours⁴ 16 hours 13 hours receiving vessel³ Duration of 7 hours 3hours 19.5 hours 13 hours filtration through Filter B Total duration of12.5 hours 17.5 hours 43.5 hours 29.5 hours entire process (totalholding time) Temperature range 10.4-12.2° C. Controlled 10.2-11.7° C.Controlled before Filter B room room temperature temperature Temperaturerange 9.3-11.0° C. Controlled 9.0-10.2° C. Controlled after Filter Broom room temperature temperature Maximum pressure 0.6 bar 0.3 bar 0.6bar 2.5 bar⁵ before Filter B Total volume filled 130 L 50 L 180 L 134 Linto syringes Storage conditions Long term Stress Long term Long termduring stability (2-8° C.) (40° C./60% RH) (2-8° C.) (2-8° C.) studiesAccelerated accelerated Accelerated (25° C./60% RH) (25° C./60% RH) (25°C./60% RH) Stress Stress Stress (40° C./60% RH) (40° C./60% RH) (40°C./60% RH) Stability data and Stability data showed that the drugproduct has a similar stability profile conclusions at all three storageconditions, regardless of whether it is filtered at controlled roomtemperature or under reduced temperature conditions. Both filtrationprocesses result in product having substantially the same degradationand impurity profile at stress conditions. ¹Batches A and A-2 are fromthe same bulk solution. Filter B was replaced with a new filter prior tofiltration of A-2. ²Compounding and subsequent holding time in thecompounding vessel (incl. filtration through filter A). ³Time from endof filtration through Filter A to beginning of filtration through FilterB and filling. ⁴Since A-2 was filtered and filled into syringessubsequent to the filtration and filling of A, the stated holding timerepresents the sum of the holding time of A in addition to the time A-2was held until the filtration at controlled room temperature wasinitiated. ⁵Throughout the filling, gradual increase of filtrationpressure was required in order to maintain flow rate that wouldcorrespond to the rate required for continuous filling.

Based on the results of Experiment No. 3, it was confirmed that localcooling by heat exchanger is sufficient in order to enable filtration ofa 130 L batch. In addition, the quality and stability profile of GA 40mg/mL solutions filtered at controlled room temperature and reducedtemperature were found to be substantially identical.

EXAMPLE 4

Cooling of GA 40 mg/mL bulk solution below 17.5° C. in the compoundingvessel before passing through cooled Filter A and cooled Filter B insequence (see FIG. 6) results in lower pressure during the filtrationstep of both Filter A and Filter B as compared to the holding the samebulk solution in the compounding vessel and passing it through Filter Aand Filter B at controlled room temperature (Cooling of the bulksolution by using double jacketed compounding vessel and cooling thefilters by using double jacketed filter housings).

Reducing the temperature of the GA 40 mg/mL bulk solution in thecompounding vessel and passing it through cooled Filter A and Filter Bin sequence (see FIG. 6) significantly reduces impairment offilterability caused by the total duration of the process (holding time)as well as by filtering larger volume, compared to the same bulksolution held and filtered under controlled room temperature.

EXAMPLE 5

Local cooling of GA 40 mg/mL bulk solution by a heat exchanger andpassing the solution through cooled Filter A and cooled Filter B insequence (see FIG. 7) results in lower pressure during the filtrationstep of both Filter A and Filter B as compared to passing the same bulksolution held and filtered under controlled room temperature.

Reducing the temperature of the GA 40 mg/mL bulk solution using a heatexchanger and passing it through cooled Filter A and cooled Filter B insequence (see FIG. 7) significantly reduces impairment of filterabilitycaused by the total duration of the process (holding time) as well as byfiltering larger volume, compared to the same bulk solution held andfiltered under controlled room temperature.

EXAMPLE 6

Passing the sterilized GA 40 mg/ml, bulk solution from the receivingvessel through cooled Filter B (see FIG. 8) significantly results inlower pressure during the filtration step compared to passing the samebulk solution filtered through Filter B under controlled roomtemperature.

Passing the sterilized GA 40 mg/mL bulk solution from the receivingvessel through cooled Filter B (see FIG. 8) significantly reducesimpairment of filterability caused by the total duration of the process(holding time) as well as by filtering larger volume, compared to thesame bulk solution held and filtered under controlled room temperature.

EXAMPLE 7

Passing GA 40 mg/mL bulk solution from the compounding vessel throughcooled Filter A and cooled Filter B in sequence (see FIG. 9) results inlower pressure during the filtration step of both Filter A and Filter Bas compared to passing the same bulk solution filtered under controlledroom temperature.

Passing GA 40 mg/mL bulk solution from the receiving vessel throughcooled Filter A and Filter B in sequence (see FIG. 9) significantlyreduces impairment of filterability caused by the total duration of theprocess (holding time) as well as by filtering larger volume, comparedto the same bulk solution filtered under controlled room temperature.

EXAMPLE 8

Cooling of GA 40 mg/mL bulk solution below 17.5° C. in the compoundingvessel before passing through Filter A and Filter B in sequence (seeFIG. 10) results in lower pressure during the filtration step of bothFilter A and Filter B as compared to the holding the same bulk solutionin the compounding vessel and passing it through Filter A and Filter Bat controlled room temperature (Cooling of the bulk solution by usingdouble jacketed compounding vessel).

Reducing the temperature of the GA 40 mg/mL bulk solution in thecompounding vessel and passing it through Filter A and Filter B inseries (see FIG. 10) significantly reduces impairment of filterabilitycaused by the total duration of the process (holding time) as well as byfiltering larger volume, compared to the same bulk solution held andunder controlled room temperature.

EXAMPLE 9

Cooling of GA 40 mg/mL bulk solution below 17.5° C. in the receivingvessel before passing through Filter B (see FIG. 11) results in lowerpressure during the filtration step of Filter 3 as compared to theholding the same bulk solution in the compounding vessel at controlledroom temperature (Cooling of the bulk solution by using double jacketedcompounding vessel).

Reducing the temperature of the GA 40 mg/mL bulk solution in thereceiving vessel (see FIG. 10) significantly reduces impairment offilterability caused by the total duration of the process (holding time)as well as by filtering larger volume, compared to the same bulksolution held under controlled room temperature.

DISCUSSION OF EXAMPLES 1-9

Reducing the temperature of GA 40 mg/mL sterile bulk solutionsignificantly improved its filterability, as demonstrated by the muchlower increase in pressure on Filter B during filtration and filling andby the larger volume that can be filtered at reduced temperature.Pressure increases were observed when the sterile bulk solution was heldand filtered at controlled room temperature, while there was nosignificant increase in the pressure when the solution was filteredunder reduced temperature conditions.

The holding time of the bulk solution during filtration through Filter Bnegatively affects the filterability of the solution. However, the totalduration of the process (holding time) impaired the filterabilitysignificantly less when filtration was performed under reducedtemperature conditions. Consequently, longer holding time can be usedwith reduced temperature filtration.

Both cooling of the solution by passing it through a heat exchanger(local cooling) and/or cooling of the whole bulk (e.g. bydouble-jacketed receiving vessel) before filtration through cooledFilters A or B or A and B were found to be suitable solutions forreduced temperature filtration.

Accumulated stability data indicate that there is no substantialdifference with regard to quality and stability profile between thesolution filtered under reduced temperature conditions and the solutionfiltered at controlled room temperature.

In sum, the performed experiments show that reduced temperaturefiltration through Filter B significantly improved the filterability ofGA 40 mg/mL solution compared to the filterability of the solution whenfiltered at controlled room temperature. Moreover, reducing thetemperature of the bulk solution during the compounding stage or beforepassing through Filter A, or reducing the temperature of Filter A alsoimproves the filterability of GA 40 mg/mL solution compared to thefilterability of the solution at controlled room temperature.

Consequently, the proposed manufacturing process for commercial batchesof GA 20 mg/mL and GA 40 mg/mL includes cooling of the solution prior tofiltration of the bulk solution through Filter B.

EXAMPLE 10 Container Closure System

The container closure systems selected for the Copaxone® 40 mg/mL arethe same as those used for the marketed product Copaxone® 20 mg/mL PES.The container closure system consists of a colorless glass barrel, aplastic plunger rod and a grey rubber stopper.

Long Term and Accelerated Stability Studies

Satisfactory stability data after up to 36 months storage underlong-term storage conditions (5° C.±3° C.) and after 6 months storageunder accelerated conditions (25°±2° C./60±5% RH) are available. Thedata demonstrate that the proposed container closure systems aresuitable for protection and maintenance of the drug product qualitythroughout its proposed shelf-life.

Protection from Light

Marketed Copaxone® should be stored protected from light. Based on thisrecommendation, it is proposed that Copaxone® 40 mg/mL be similarlypacked in PVC transparent blisters inside a carton box, which provideslight protection. The light protection of the proposed packaging whenused for the Copaxone® 40 mg/mL is recommended in accordance with theresults obtained from a photostability study comparing the followingpackaging configurations:

1. Glass barrel syringe and plunger rod (Primary package);

-   -   Glass barrel syringe and plunger rod in a transparent blister        (partial secondary package);    -   Glass barrel syringe and plunger rod in a transparent blister        inside carton box (complete intended packaging configuration).

As a reference, the following configurations were added:

2. Glass barrel syringe and plunger rod wrapped in aluminum foil;

-   -   Glass barrel and plunger rod in a transparent blister wrapped in        aluminum foil.

All packages were simultaneously exposed to standardized sunlight (5KLUX) for 10 days and to near UV light for additional 5 days.

All the obtained results from the photostability study are within thespecifications. However, the impurity peak detected is lower when thedrug product is packed in its complete packaging configuration. Thecarton box was shown to improve the photostability and gives lightprotection as good as that of aluminum foil, which is regarded as acomplete light protector. The intended packaging configuration istherefore considered suitable for its use.

A storage statement to protect the product from light exposure should beadded to the product label.

Microbiological Attributes

The medicinal product is a sterile, single dose, parenteral dosage form.Sterilization is achieved by sterile filtration.

A microbial limits test is performed for the drug substance. Thesterility and bacterial endotoxins are monitored upon release andthroughout stability studies of the drug product, using pharmacopoeiamethods. The limits applied are identical to those applied for themarketed Copaxone®.

The same container closure systems are used for the Copaxone® 20 mg/mLand Copaxonee 40 mg/mL. The integrity testing studies performed todemonstrate the efficacy of the container closure systems on use for themarketed product are also considered relevant for Copaxone® 40 mg/mL.

EXAMPLE 11 Viscosity

The average viscosity of batches of Copaxone® 20 mg/mL filtered undercontrolled room temperature and the average viscosity of batches ofCopaxone® 40 mg/mL filtered under reduced temperature were obtained andcompared. The average viscosity of different batches of Copaxone® 20mg/mL filtered under controlled room temperature are reported in Table5. The average viscosity of different batches of Copaxone® 40 mg/mLfiltered under reduced temperature are reported in Table 6.

TABLE 5 Viscosity of Batches of Copaxone ® 20 mg/mL Filtered UnderControlled Room Temperature Average Standard Batch No. Viscosity [cPa]Deviation 1 1.92¹ 0.03 2 1.58¹ 0.00 3 1.58¹ 0.00 4 1.57² 0.00 5 1.67²0.01 Water for 0.93² 0.00 Injection Average 1.664 ¹Each value is anaverage of 3 individual results. Values obtained using Rheocalc V2.5Model LV, Spindle CP40, speed 80 rpm, Shear Rate 600 1/sec, Temperature25° C. ± 0.1 ²Each value is an average of 6 individual results. Valuesobtained using Rheocalc V2.5 Model LV, Spindle CP40, speed 80 rpm, ShearRate 600 1/sec, Temperature 25° C. ± 0.1

TABLE 6 Viscosity of Batches of Copaxone ® 40 mg/mL Filtered UnderReduced Temperature Average Standard Batch No. Viscosity [cPa]¹Deviation 1 2.82 0.000 2 2.92 0.008 3 2.91 0.010 4 2.61 0.012 5 2.610.004 6 2.73 0.021 7 2.61 0.016 Average 2.743 0.007 ¹Each value is anaverage of 6 individual results. Values obtained using Rheocalc V2.5Model LV, Spindle CP40, speed 80 rpm, Shear Rate 600 1/sec, Temperature25° C. ± 0.1

Osmolality

The osmolality of batches of Copaxone® 20 mg/mL filtered undercontrolled room temperature and the osmolality of batches of Copaxone®40 mg/ml, filtered under reduced temperature were measured.

Samples from each batch were tested in triplicates. The results arereported in Table 7.

TABLE 7 Osmolality of Batches of Copaxone ® 20 mg/mL Filtered UnderControlled Room Temperature and Batches of Copaxone ® 40 mg/mL FilteredUnder Reduced Temperature Relative Standard Mannitol Average DeviationBatch No. GA Dose Dose Osmolality (RSD) Copaxone ® 40 mg/ml 40 mg/ml 303mosmol/Kg 1.2 40 mg/mL No. 1 Copaxone ® 40 mg/ml 40 mg/ml 300¹mosmol/Kg  1.7 40 mg/mL No. 2 Copaxone ® 40 mg/ml 40 mg/ml 302 mosmol/Kg2.1 40 mg/mL No. 3 Copaxone ® 20 mg/ml 40 mg/ml 268 mosmol/Kg 2.6 20mg/mL No. 1 Copaxone ® 20 mg/ml 40 mg/ml 264 mosmol/Kg 1.2 20 mg/mL No.2 Placebo  0 mg/ml 40 mg/ml 227 mosmol/Kg 0 ¹Calculated from 4measurements.

The results show that the osmolality of batches of Copaxone® 40 mg/mLwere well within the ranges of an isotonic solution. The results alsoshow that the batches of Copaxone® 40 mg/mL conformed to the generalparenteral drug product osmolality limits of 300±30 mosmol/Kg. Further,the results indicate that batches of Copaxone® 20 mg/mL were slightlyhypotonic.

What is claimed:
 1. A process of preparing a pharmaceutical preparationof glatiramer acetate and mannitol in a suitable container comprisingthe steps of: (i) obtaining an aqueous pharmaceutical solution ofglatiramer acetate and mannitol; (ii) filtering the aqueouspharmaceutical solution at a temperature of from above 0° C. up to 17.5°C. to produce a filtrate; and (iii) filling the suitable container withthe filtrate obtained after performing step (ii), so as to therebyprepare the pharmaceutical preparation of glatiramer acetate andmannitol in the suitable container.
 2. The process of claim 1, whereinthe filtering step (ii) comprises filtering the aqueous pharmaceuticalsolution through a first filter, or a first filter and a second filter.3. The process of claim 2 further comprising the step of reducing thetemperature of the second filter to a temperature from above 0° C. up to17.5° C.
 4. The process of claim 2 or claim 3 further comprising thestep of reducing the temperature of the aqueous pharmaceutical solutionto a temperature from above 0° C. up to 17.5° C. before passing throughthe second filter.
 5. The process of any one of claims 2-4, wherein thefiltering step (ii) further comprises the step of receiving the aqueouspharmaceutical solution filtered through the first filter in a receivingvessel.
 6. The process of claim 5 further comprising the step ofreducing the temperature of the aqueous pharmaceutical solution to atemperature from above 0° C. up to 17.5° C. after leaving the receivingvessel and before entering into the second filter.
 7. The process ofclaim 5 or claim 6 further comprising the step of reducing thetemperature of the aqueous pharmaceutical solution to a temperature fromabove 0° C. up to 17.5° C. while in the receiving vessel.
 8. The processof any one of claims 2-7 further comprising the step of reducing thetemperature of the first filter to a temperature from above 0° C. up to17.5° C.
 9. The process of any one of claims 2-8 further comprising thestep of reducing the temperature of the aqueous pharmaceutical solutionto a temperature from above 0° C. up to 17.5° C. before passing throughthe first filter.
 10. The process of any one of claims 2-9, wherein theobtaining step (i) comprises compounding the aqueous pharmaceuticalsolution in a compounding vessel.
 11. The process of claim 10 furthercomprising the step of reducing the temperature of the aqueouspharmaceutical solution to a temperature from above 0° C. up to 17.5° C.after leaving the compounding vessel and before entering into the firstfilter.
 12. The process of claim 10 or claim 11 further comprising thestep of reducing the temperature of the aqueous pharmaceutical solutionto a temperature from above 0° C. up to 17.5° C. while in thecompounding vessel.
 13. The process of any one of claims 2-14, whereinthe aqueous pharmaceutical solution is passed through the second filterat a rate of 3-25 liters/hour; preferably at a rate of 3-22 liters/hour;more preferably at a rate of 3-15 liters/hour; or more preferably at arate of 3-10 liters/hour.
 14. The process of any one of claims 1-12,wherein the pressure during the filtering step (ii) and the pressureduring the filling step (iii) is maintained below 5.0 bar; or preferablybelow 3.0 bar.
 15. The process of any one of claims 1-13, wherein thepressure during the filtering step (ii) and the pressure during thefilling step (iii) is maintained below 2.0 bar.
 16. The process of anyone of claims 1-15, wherein the temperature of the aqueouspharmaceutical solution is between 0° C. and 14° C., or the temperatureof the aqueous pharmaceutical solution is reduced to a temperaturebetween 0° C. and 14° C.
 17. The process of any one of claims 1-15,wherein the temperature of the aqueous pharmaceutical solution isbetween 0° C. and 12° C., or the temperature of the aqueouspharmaceutical solution is reduced to a temperature between 0° C. and12° C.
 18. The process of any one of claims 1-15, wherein thetemperature of the aqueous pharmaceutical solution is 2° C. -12° C., orthe temperature of the aqueous pharmaceutical solution is reduced to 2°C.-12° C.
 19. The process of any one of claims 1-15, wherein thetemperature of the aqueous pharmaceutical solution is 4° C.-12° C., orthe temperature of the aqueous pharmaceutical solution is reduced to 4°C.-12° C.
 20. The process of any one of claims 1-19, wherein thefiltering is performed using a sterilizing filter having a pore size of0.2 μm or less, wherein the first, the second or both filters are asterilizing filter having a pore size of 0.2 μm or less.
 21. The processof any one of claims 1-20, wherein the pharmaceutical preparation in thesuitable container is an aqueous pharmaceutical solution comprising 20mg/ml glatiramer acetate and 40 mg/ml mannitol.
 22. The process of anyone of claims 1-20, wherein the pharmaceutical preparation in thesuitable container is an aqueous pharmaceutical solution comprising 40mg/ml glatiramer acetate and 40 mg/ml mannitol.
 23. The process of anyone of claims 1-22, wherein the pharmaceutical preparation in thesuitable container is an aqueous pharmaceutical solution having a pH inthe range of 5.5-7.0.
 24. The process of any one of claims 1-23, whereinthe pharmaceutical preparation in the suitable container is an aqueouspharmaceutical solution which is a sterilized aqueous solution which hasbeen sterilized by filtration and without subjecting the aqueouspharmaceutical solution to heat, chemicals, or radiation exposure. 25.The process of any one of claims 1-20, wherein the pharmaceuticalpreparation is a lyophilized powder of glatiramer acetate and mannitol.26. The process of any one of claim 1-20 or 25 further comprising a stepof lyophilizing the filtrate after it has been filled into the suitablecontainer so as to form a lyophilized powder of glatiramer acetate andmannitol in the suitable container.
 27. The process of any one of claims1-26, wherein the suitable container is a syringe, vial, ampoule,cartridge or infusion.
 28. The process of claim 27, wherein the suitablecontainer is a syringe.
 29. The process of claim 28, wherein the syringecontains 1 ml of an aqueous pharmaceutical solution.
 30. A prefilledsyringe containing 40 mg of glatiramer acetate and 40 mg mannitol, whichsyringe is prepared by the process of any one of claims 1-29.
 31. Theprefilled syringe of claim 30, wherein the prefilled syringe contains 1ml of an aqueous pharmaceutical solution of 40 mg/ml of glatirameracetate and 40 mg/ml mannitol.
 32. The prefilled syringe of claim 31,wherein the aqueous pharmaceutical solution a) has a viscosity in therange of 2.0-3.5 cPa; or b) has an osmolality in the range of 270-330mosmol/Kg.
 33. The prefilled syringe of claim 32, wherein the aqueouspharmaceutical solution a) has a viscosity in the range of 2.2-3.0 cPa;or b) has an osmolality in the range of 275-325 mosmol/Kg.
 34. Anaqueous pharmaceutical solution comprising 40 mg/ml glatiramer acetateand 40 mg/ml mannitol, wherein the aqueous pharmaceutical solution a)has a viscosity in the range of 2.0-3.5 cPa; or b) has an osmolality inthe range of 275-325 mosmol/Kg.
 35. The aqueous pharmaceutical solutionof claim 34, wherein the aqueous pharmaceutical solution has a viscosityin the range of 2.0-3.5 cPa.
 36. The aqueous pharmaceutical solution ofclaim 34 or 35, wherein the aqueous pharmaceutical solution has aviscosity in the range of 2.61-2.92 cPa.
 37. The aqueous pharmaceuticalsolution of claim 34, wherein the aqueous pharmaceutical solution has anosmolality in the range of 275-325 mosmol/Kg.
 38. The aqueouspharmaceutical solution of any one of claims 34-37, wherein the aqueouspharmaceutical solution has an osmolality in the range of 300-303mosmol/Kg.
 39. The aqueous pharmaceutical solution of any one of claims34-38, wherein the aqueous pharmaceutical solution has a pH in the rangeof 5.5-7.0.
 40. A prefilled syringe containing 1 ml of the aqueouspharmaceutical solution of any one of claims 34-39.
 41. An automatedinjector comprising the prefilled syringe of any one of claim 30-33 or40.
 42. A method of treatment of a human patient suffering from arelapsing form of multiple sclerosis comprising administration to thehuman patient of three subcutaneous injections of a 40 mg/ml dose ofglatiramer acetate per week using the prefilled syringe of any one ofclaim 30-33 or 40, using the aqueous pharmaceutical solution of any oneof claims 34-39, or using the automated injector of claim 41 so as totreat the human patient.
 43. The method of claim 42, wherein the humanpatient is suffering from relapsing-remitting multiple sclerosis. 44.The method of claim 42, wherein the human patient has experienced afirst clinical episode and has MRI features consistent with multiplesclerosis.